US4483861A - Antihypertensive sulfur-containing compounds - Google Patents
Antihypertensive sulfur-containing compounds Download PDFInfo
- Publication number
- US4483861A US4483861A US06/086,996 US8699679A US4483861A US 4483861 A US4483861 A US 4483861A US 8699679 A US8699679 A US 8699679A US 4483861 A US4483861 A US 4483861A
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- United States
- Prior art keywords
- sub
- substituted
- compound
- groups
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 60
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 title claims abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 title claims abstract description 6
- 239000011593 sulfur Substances 0.000 title claims abstract description 6
- 230000003276 anti-hypertensive effect Effects 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 8
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- 230000036772 blood pressure Effects 0.000 claims abstract 3
- -1 nitro, amino Chemical group 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 125000001589 carboacyl group Chemical group 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 16
- 125000004442 acylamino group Chemical group 0.000 claims description 13
- 125000004423 acyloxy group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000003282 alkyl amino group Chemical group 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 6
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 5
- 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 3
- XNWRFHDIFVKSNS-UHFFFAOYSA-N 2-(2-acetyloxyphenyl)-3-(3-acetylsulfanylpropanoyl)-1,3-thiazolidine-4-carboxylic acid Chemical compound CC(=O)OC1=CC=CC=C1C1N(C(=O)CCSC(C)=O)C(C(O)=O)CS1 XNWRFHDIFVKSNS-UHFFFAOYSA-N 0.000 claims description 3
- 125000001769 aryl amino group Chemical group 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 229950001139 timonacic Drugs 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 4
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 4
- NKLCHDQGUHMCGL-UHFFFAOYSA-N cyclohexylidenemethanone Chemical group O=C=C1CCCCC1 NKLCHDQGUHMCGL-UHFFFAOYSA-N 0.000 claims 3
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims 2
- GKLYKLDSPANDAP-ZSOXZCCMSA-N (4r)-2-(2-methoxyphenyl)-3-(3-methylsulfanylpropanoyl)-1,3-thiazolidine-4-carboxylic acid Chemical compound COC1=CC=CC=C1C1N(C(=O)CCSC)[C@H](C(O)=O)CS1 GKLYKLDSPANDAP-ZSOXZCCMSA-N 0.000 claims 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims 1
- 125000001999 4-Methoxybenzoyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C(*)=O 0.000 claims 1
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- 125000005236 alkanoylamino group Chemical group 0.000 claims 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims 1
- 125000001188 haloalkyl group Chemical group 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 150000007513 acids Chemical class 0.000 abstract description 8
- 150000002148 esters Chemical class 0.000 abstract description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
- 101150035983 str1 gene Proteins 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 219
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 56
- 235000019439 ethyl acetate Nutrition 0.000 description 23
- 239000000243 solution Substances 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 12
- 239000008101 lactose Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 125000003396 thiol group Chemical class [H]S* 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 229940030600 antihypertensive agent Drugs 0.000 description 7
- 239000002220 antihypertensive agent Substances 0.000 description 7
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000001913 cellulose Substances 0.000 description 6
- 229920002678 cellulose Polymers 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000008119 colloidal silica Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 101800000734 Angiotensin-1 Proteins 0.000 description 5
- 102400000344 Angiotensin-1 Human genes 0.000 description 5
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 230000036584 pressor response Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 4
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
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- 229940126208 compound 22 Drugs 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
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- 238000012360 testing method Methods 0.000 description 4
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 3
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 3
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
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- KJZBTXPCZLHWHN-FTNKSUMCSA-N (4r)-2-(2-acetyloxyphenyl)-1,3-thiazolidine-4-carboxylic acid Chemical compound CC(=O)OC1=CC=CC=C1C1SC[C@@H](C(O)=O)N1 KJZBTXPCZLHWHN-FTNKSUMCSA-N 0.000 description 2
- FWNWATHTRVGPDX-RITPCOANSA-N (4r)-3-[(2s)-2-methyl-3-sulfanylpropanoyl]-1,3-thiazolidine-4-carboxylic acid Chemical compound SC[C@@H](C)C(=O)N1CSC[C@H]1C(O)=O FWNWATHTRVGPDX-RITPCOANSA-N 0.000 description 2
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- RLPBLYOMUDFEBW-PWSUYJOCSA-N (4r)-3-[(2s)-3-benzoylsulfanyl-2-methylpropanoyl]-1,3-thiazolidine-4-carboxylic acid Chemical compound C([C@@H](C)C(=O)N1[C@@H](CSC1)C(O)=O)SC(=O)C1=CC=CC=C1 RLPBLYOMUDFEBW-PWSUYJOCSA-N 0.000 description 1
- GPBXPZUMIAJSMY-ZBFHGGJFSA-N 2,2-dimethylpropanoyloxymethyl (4r)-3-[(2s)-3-benzoylsulfanyl-2-methylpropanoyl]-1,3-thiazolidine-4-carboxylate Chemical compound C([C@@H](C)C(=O)N1[C@@H](CSC1)C(=O)OCOC(=O)C(C)(C)C)SC(=O)C1=CC=CC=C1 GPBXPZUMIAJSMY-ZBFHGGJFSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- QCXJEYYXVJIFCE-UHFFFAOYSA-N 4-acetamidobenzoic acid Chemical compound CC(=O)NC1=CC=C(C(O)=O)C=C1 QCXJEYYXVJIFCE-UHFFFAOYSA-N 0.000 description 1
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 101100177155 Arabidopsis thaliana HAC1 gene Proteins 0.000 description 1
- 241000725101 Clea Species 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101100434170 Oryza sativa subsp. japonica ACR2.1 gene Proteins 0.000 description 1
- 101100434171 Oryza sativa subsp. japonica ACR2.2 gene Proteins 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 101150108015 STR6 gene Proteins 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- CJCSPKMFHVPWAR-JTQLQIEISA-N alpha-methyl-L-dopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 1
- 229960004064 bumetanide Drugs 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000007073 chemical hydrolysis Effects 0.000 description 1
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 description 1
- 229960003199 etacrynic acid Drugs 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- ACGDKVXYNVEAGU-UHFFFAOYSA-N guanethidine Chemical compound NC(N)=NCCN1CCCCCCC1 ACGDKVXYNVEAGU-UHFFFAOYSA-N 0.000 description 1
- 229960003602 guanethidine Drugs 0.000 description 1
- 229960002474 hydralazine Drugs 0.000 description 1
- DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 description 1
- 229960003313 hydroflumethiazide Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 235000021401 pellet diet Nutrition 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 206010038464 renal hypertension Diseases 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- HYQSTIMJGAYUGG-UHFFFAOYSA-N s-(3-chloro-3-oxopropyl) 4-methylbenzenecarbothioate Chemical compound CC1=CC=C(C(=O)SCCC(Cl)=O)C=C1 HYQSTIMJGAYUGG-UHFFFAOYSA-N 0.000 description 1
- XEYWOETXQNDSED-UHFFFAOYSA-N s-(3-chloro-3-oxopropyl) ethanethioate Chemical compound CC(=O)SCCC(Cl)=O XEYWOETXQNDSED-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- This invention relates to sulfur-containing compounds which are useful as antihypertensive agents. These compounds are represented by the following formula [I] and salts thereof. ##STR2## wherein
- Q is methylene or sulfur
- R a is R 1 or R 9 ;
- R b is R 2 , R 4 , R 6 , R 8 or R 10 ;
- R c is R 3 , R 5 or R 7 ;
- R b is R 2 , R 4 or R 10 , and R c is R 3 or R 5 ;
- R b is R 6 , R 8 or R 10 , and R c is R 5 or R 7 ;
- R b is R 2 , R c is R 3 ; when R b is R 4 or R 8 , R c is R 5 ; when R b is R 6 , R c is R 7 ; when R b is R 10 , R c is R 5 , and R a is R 9 ;
- R 1 is hydrogen
- R 2 is lower alkyl, aralkyl, lower alkanoyl, cycloalkanecarbonyl, phenyl-lower alkanoyl, pyridylcarbonyl, benzyloxycarbonyl, substituted benzoyl or substituted phenyl-lower alkanoyl wherein the substituent(s) is lower alkyl, halogen or lower alkoxy;
- R 3 is higher alkyl, cycloalkyl, aralkyl, phenyl, furyl, thienyl, pyridyl, naphthyl, substituted higher alkyl, substituted cycloalkyl, substituted aralkyl, substituted phenyl, substituted furyl, substituted thienyl, substituted pyridyl or substituted naphthyl wherein the substituent(s) is lower alkyl, hydroxy, lower alkoxy, acyloxy, mercapto, acylmercapto, halogen, nitro, amino, lower alkylamino, acylamino, lower alkylenedioxy or carboxy;
- R 4 is higher alkanoyl, naphtoyl, ##STR3## substituted lower alkyl, substituted benzoyl or substituted phenyl-lower alkanoyl wherein the substituent(s) is hydroxy, phenyl-lower alkoxy, acyloxy, mercapto, acylmercapto, nitro, amino, lower alkylamino, acylamino or carboxy;
- R 5 is hydrogen, lower alkyl, higher alkyl, cycloalkyl, aralkyl, phenyl, furyl, thienyl, pyridyl, naphthyl, substituted lower alkyl, substituted higher alkyl, substituted cycloalkyl, substituted aralkyl, substituted phenyl, substituted furyl, substituted thienyl, substituted pyridyl or substituted naphthyl wherein the substituent(s) is lower alkyl, hydroxy, lower alkoxy, acyloxy, mercapto, acylmercapto, halogen, nitro, amino, lower alkylamino, acylamino, lower alkylenedioxy or carboxy;
- R 6 is acetyl
- R 7 is higher alkyl, cycloalkyl, aralkyl, furyl, thienyl, pyridyl, naphthyl or substituted phenyl wherein the substituent(s) is acyloxy, mercapto, acylmercapto, amino, lower alkylamino, acylamino, lower alkylenedioxy or carboxy;
- R 8 is lower alkyl, lower alkanoyl except acetyl, higher alkanoyl, cycloalkanecarbonyl, aralkyl, phenyl-lower alkanoyl, pyridylcarbonyl, benzyloxycarbonyl, naphtoyl, ##STR4## substituted lower alkyl, substituted benzoyl or substituted phenyl-lower alkanoyl wherein the substituent(s) is lower alkyl, lower alkoxy, hydroxy, phenyl-lower alkoxy, acyloxy, halogen, mercapto, acylmercapto, nitro, amino, lower alkylamino, arylamino, acylamino or carboxy;
- R 9 is phenyl, alkoxy-lower alkyl, acyloxy-lower alkyl, imido-lower alkyl or substituted phenyl wherein the substituent(s) is lower alkyl, lower alkoxy, hydroxy, acyl, acyloxy, halogen, nitro, amino, lower alkylamino, acylamino or carboxy;
- R 10 is lower alkyl, lower alkanoyl, higher alkanoyl, cycloalkanecarbonyl, aralkyl, benzoyl, phenyl-lower alkanoyl, pyridylcarbonyl, benzyloxycarbonyl, naphtoyl, ##STR5## substituted lower alkyl, substituted benzoyl or substituted phenyl-lower alkanoyl wherein the substituent(s) is lower alkyl, lower alkoxy, hydroxy, phenyl-lower alkoxy, acyloxy, halogen, mercapto, acylmercapto, nitro, amino, lower alkylamino, acylamino or carboxy;
- Z is straight or branched alkylene with 1 to 3 carbon atoms (e.g., --CH 2 --, --CH(CH 3 )--, --CH 2 CH 2 --, --CH(CH 3 )(CH 2 --); in the formula,
- lower alkyl or lower alkylene is straight or branched chain with 1 to 6 carbion atoms
- higher alkyl is saturated or unsaturated, straight or branched chain with 7 to 20 carbon atoms
- aralkyl is benzyl, etc.
- acyl is acetyl, propionyl, pivaloyl, etc.
- lower alkanoyl is acetyl, propionyl, pivaloyl, etc.
- alkanoyl is octanoyl, linoloyl, etc.
- lower alkoxy is methoxy, ethoxy, etc.
- aryl is 3-trifluoromethylphenyl, etc.
- imido is succinimido, phthalimido, etc.
- the compounds [I] of this invention are ester derivatives and/or S-acyl or S-alkyl derivatives of mercaptoacylamino acids, the known effective angiotensin I-converting enzyme inhibitors, and they release mercaptoacylamino acids which are proved efficacious at the part to be shown the activity by enzymatic and/or chemical hydrolysis when administered to men or animals.
- Mercaptoacylamino acid is easy to be subjected to the reactions such as oxidation, etc. during the manufacture thereof or with time lapse in the living body because it contains sulfhydryl group in its molecule, and therefore possesses the problems, that is, the decrease in activity and shorter effective hours.
- the protection of sulfhydryl group by acyl particularly benzoyl can make the activity long lasting ans simultaneously the lipophilic property increase, and therefore the absorption potency can be improved.
- the effective time cannot be prolonged to a desirable extent because they are immediately deacylated by hydrolysis or metabolism in the living body after absorbed.
- various substituents are introduced to benzoyl group as acyl group protecting the sulfhydryl group in mercaptoacylamino acid. As the result, it has been proved that the compounds of this invention can make the effective time longer than S-benzoyl derivatives.
- esterification of carboxylic acid can also increase the lipophilic property of mercaptoacylamino acid, and therefore the absorption potency can be further improved and the activity can be further prolonged.
- thioester of mercaptoacylamino acid and various diuretic such as ethacrynic acid and furosemide, etc. is also efficacious.
- the compounds of this invention have the property that the activity is hard to decrease particularly by oxidation, etc., and the medicinal preparation is more stable than the antihypertensive compositions containing the known mercaptoacylamino acids as main ingredient so that it may not show the lowering of activity, or the generation of offensive odor, etc. through decomposition during the manufacture thereof or with time lapse.
- the compounds [I] of this invention are synthesized by such methods as the following A, B and C.
- the compounds of the formula [I] synthesized by the above methods can form the conventional salts to be generally used as medicine such as sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, diethylamine salt, triethanolamine salt, etc.
- the compounds of the formula [I] have the stereoisomers which are within the limit of this invention, because they have one or more asymmetric carbon atoms.
- IR (nujol, cm -1 ) 1766, 1650, 1620, 1605, 1428, 1215, 1208, 1174, 913.
- IR (nujol, cm -1 ) 3286, 1735, 1645, 1622, 1585, 1524, 1455, 1318, 1210, 1170, 913.
- Tables I to VIII show various compounds and physical constants including the compounds specified in the examples.
- Table IX shows the results of the pharmacological tests when the represented compounds of the compounds [I] of this invention and the related salts are used as antihypertensive agents. Table IX clearly shows that the compounds of this invention have the long-lasting, useful antihypertensive effect, and stability is also excellent.
- the compounds inhibiting angiotensin I-converting enzyme may be the curative potency against both renal hypertension and essential hypertension
- the compounds of this invention are evaluated as antihypertensive agents by the following method.
- the compounds of this invention suspended in 0.5% tragacanth solution are administered orally in a dose of 0.3 ml per 100 g of body weight, and the pressor response to angiotensin I infused intravenously is measured with time.
- the inhibitory activity of the compounds against angiotensin I-converting enzyme is expressed as the percent inhibition of pressor response to angiotensin I.
- Table IX shows the changes of percent inhibition of the compounds of this invention with time.
- the compounds of this invention as well as the known antihypertensive mercaptoacylamino acids suppress the pressor response to angiotensin I by administered orally to unanesthesized rats, the mechanism of which is derived from inhibiting angiotensin I-converting enzyme.
- the compounds of this invention are derivatives of mercaptoacylamino acid, and with the comparative result in the suppressive effect of pressor response to angiotensin I by administering these equimolar compounds orally it has been proved that the compounds of this invention are well absorbed from the gastroenteric wall, and hydrolyzed gradually at the part to be shown the activity so that they have the advantages as antihypertensive agent such as durability.
- the stability of mercaptoacylamino acids is compared with that of ester derivatives or S-acyl and S-alkyl derivatives in the ethanol or the phosphate buffer solution (pH 7.0).
- Condition for preservation at room temperature, for 1 month.
- Ester derivatives and S-acyl and S-alkyl derivatives are more stable than mercaptoacylamino acids.
- mice The male ddy-std. strain mice (4 weeks of age, weighing 19-21 g) were placed in a breeding room of constant temperature and humidity (23 ⁇ 1° C., 55 ⁇ 5%) and fed freely pellet diet (CE-2, Clea Japan, Inc.) and water ad. libitum for a week. The mice showing the normal growth were selected for the experiment.
- Test compound is suspended in 0.5% tragacanth solution, and administered intraperitoneally in a dose of 0.5 ml per 20 g B.W.
- the compounds [I] to [V] of this invention are useful as antihypertensive agents having the lasting property.
- the compounds can be given with the combination of diuretics such as hydroflumethiazide, furosemide, and bumetanide same as other antihypertensive agents.
- the compounds can be administered either orally or parenterally.
- the dosage forms are tablet, capsule, granule, powder, suppository, injection, etc. In the treatment of hypertension, these preparations can contain not only general excipients but also other antihypertensive agents such as reserpine, ⁇ -methyldopa, guanethidine, clonidine, hydralazine, etc.
- the dose is adjusted depending on symptom, dosage form, etc. But, usual daily dosage is 1 to 5000 mg, preferably 10 to 1000 mg, in one or a few divided doses.
- the tablets may be treated with common film-coating and further with sugar-coating.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
Novel S-substituted mercapto-lower alkanoyl-4-thiazolidinecarboxylic acids, -2-pyrrolidinecarboxylic acids and their esters represented by the general formula ##STR1## wherein Q is methylene or sulfur;
Z is straight or branched alkylene with 1 to 3 carbon atoms,
their process for manufacturing, the antihypertensive composition comprising these compounds and the method for reducing blood pressure.
Description
This invention relates to sulfur-containing compounds which are useful as antihypertensive agents. These compounds are represented by the following formula [I] and salts thereof. ##STR2## wherein
Q is methylene or sulfur;
Ra is R1 or R9 ;
Rb is R2, R4, R6, R8 or R10 ;
Rc is R3, R5 or R7 ;
but when Q is methylene, Rb is R2, R4 or R10, and Rc is R3 or R5 ;
when Q is sulfur, Rb is R6, R8 or R10, and Rc is R5 or R7 ;
and when Rb is R2, Rc is R3 ; when Rb is R4 or R8, Rc is R5 ; when Rb is R6, Rc is R7 ; when Rb is R10, Rc is R5, and Ra is R9 ;
R1 is hydrogen;
R2 is lower alkyl, aralkyl, lower alkanoyl, cycloalkanecarbonyl, phenyl-lower alkanoyl, pyridylcarbonyl, benzyloxycarbonyl, substituted benzoyl or substituted phenyl-lower alkanoyl wherein the substituent(s) is lower alkyl, halogen or lower alkoxy;
R3 is higher alkyl, cycloalkyl, aralkyl, phenyl, furyl, thienyl, pyridyl, naphthyl, substituted higher alkyl, substituted cycloalkyl, substituted aralkyl, substituted phenyl, substituted furyl, substituted thienyl, substituted pyridyl or substituted naphthyl wherein the substituent(s) is lower alkyl, hydroxy, lower alkoxy, acyloxy, mercapto, acylmercapto, halogen, nitro, amino, lower alkylamino, acylamino, lower alkylenedioxy or carboxy;
R4 is higher alkanoyl, naphtoyl, ##STR3## substituted lower alkyl, substituted benzoyl or substituted phenyl-lower alkanoyl wherein the substituent(s) is hydroxy, phenyl-lower alkoxy, acyloxy, mercapto, acylmercapto, nitro, amino, lower alkylamino, acylamino or carboxy;
R5 is hydrogen, lower alkyl, higher alkyl, cycloalkyl, aralkyl, phenyl, furyl, thienyl, pyridyl, naphthyl, substituted lower alkyl, substituted higher alkyl, substituted cycloalkyl, substituted aralkyl, substituted phenyl, substituted furyl, substituted thienyl, substituted pyridyl or substituted naphthyl wherein the substituent(s) is lower alkyl, hydroxy, lower alkoxy, acyloxy, mercapto, acylmercapto, halogen, nitro, amino, lower alkylamino, acylamino, lower alkylenedioxy or carboxy;
R6 is acetyl;
R7 is higher alkyl, cycloalkyl, aralkyl, furyl, thienyl, pyridyl, naphthyl or substituted phenyl wherein the substituent(s) is acyloxy, mercapto, acylmercapto, amino, lower alkylamino, acylamino, lower alkylenedioxy or carboxy;
R8 is lower alkyl, lower alkanoyl except acetyl, higher alkanoyl, cycloalkanecarbonyl, aralkyl, phenyl-lower alkanoyl, pyridylcarbonyl, benzyloxycarbonyl, naphtoyl, ##STR4## substituted lower alkyl, substituted benzoyl or substituted phenyl-lower alkanoyl wherein the substituent(s) is lower alkyl, lower alkoxy, hydroxy, phenyl-lower alkoxy, acyloxy, halogen, mercapto, acylmercapto, nitro, amino, lower alkylamino, arylamino, acylamino or carboxy;
R9 is phenyl, alkoxy-lower alkyl, acyloxy-lower alkyl, imido-lower alkyl or substituted phenyl wherein the substituent(s) is lower alkyl, lower alkoxy, hydroxy, acyl, acyloxy, halogen, nitro, amino, lower alkylamino, acylamino or carboxy;
R10 is lower alkyl, lower alkanoyl, higher alkanoyl, cycloalkanecarbonyl, aralkyl, benzoyl, phenyl-lower alkanoyl, pyridylcarbonyl, benzyloxycarbonyl, naphtoyl, ##STR5## substituted lower alkyl, substituted benzoyl or substituted phenyl-lower alkanoyl wherein the substituent(s) is lower alkyl, lower alkoxy, hydroxy, phenyl-lower alkoxy, acyloxy, halogen, mercapto, acylmercapto, nitro, amino, lower alkylamino, acylamino or carboxy;
Z is straight or branched alkylene with 1 to 3 carbon atoms (e.g., --CH2 --, --CH(CH3)--, --CH2 CH2 --, --CH(CH3)(CH2 --); in the formula,
lower alkyl or lower alkylene is straight or branched chain with 1 to 6 carbion atoms;
higher alkyl is saturated or unsaturated, straight or branched chain with 7 to 20 carbon atoms;
aralkyl is benzyl, etc.;
acyl is acetyl, propionyl, pivaloyl, etc.;
lower alkanoyl is acetyl, propionyl, pivaloyl, etc.;
higher alkanoyl is octanoyl, linoloyl, etc.;
lower alkoxy is methoxy, ethoxy, etc.;
aryl is 3-trifluoromethylphenyl, etc.;
imido is succinimido, phthalimido, etc.
The same shall be applied hereinafter.
The compounds [I] of this invention are ester derivatives and/or S-acyl or S-alkyl derivatives of mercaptoacylamino acids, the known effective angiotensin I-converting enzyme inhibitors, and they release mercaptoacylamino acids which are proved efficacious at the part to be shown the activity by enzymatic and/or chemical hydrolysis when administered to men or animals. Mercaptoacylamino acid is easy to be subjected to the reactions such as oxidation, etc. during the manufacture thereof or with time lapse in the living body because it contains sulfhydryl group in its molecule, and therefore possesses the problems, that is, the decrease in activity and shorter effective hours. On the other hand, the protection of sulfhydryl group by acyl particularly benzoyl can make the activity long lasting ans simultaneously the lipophilic property increase, and therefore the absorption potency can be improved. But, in the known S-benzoyl derivatives, the effective time cannot be prolonged to a desirable extent because they are immediately deacylated by hydrolysis or metabolism in the living body after absorbed. So, in this invention, to achieve the aim at lasting the effect as long as possible, various substituents are introduced to benzoyl group as acyl group protecting the sulfhydryl group in mercaptoacylamino acid. As the result, it has been proved that the compounds of this invention can make the effective time longer than S-benzoyl derivatives. Furthermore, esterification of carboxylic acid can also increase the lipophilic property of mercaptoacylamino acid, and therefore the absorption potency can be further improved and the activity can be further prolonged. In addition, thioester of mercaptoacylamino acid and various diuretic such as ethacrynic acid and furosemide, etc. is also efficacious. Besides, as the unstable sulfhydryl group is protected by acyl or alkyl group, the compounds of this invention have the property that the activity is hard to decrease particularly by oxidation, etc., and the medicinal preparation is more stable than the antihypertensive compositions containing the known mercaptoacylamino acids as main ingredient so that it may not show the lowering of activity, or the generation of offensive odor, etc. through decomposition during the manufacture thereof or with time lapse.
The compounds [I] of this invention are synthesized by such methods as the following A, B and C.
(A) The compounds represented by the formula
R.sup.b --S--Z--Z--CO--X [II]
wherein X is hydroxy or halogen; the same shall be applied hereinafter
are reacted with the compounds represented by the formula ##STR6## by a known method such as Schotten-Baumann reaction and mixed anhydride method to give the compounds of this invention represented by the formula [I].
(B) The compounds represented by the formula
R.sup.b --X [IV]
are reacted with the compounds represented by the formula ##STR7## by a known method such as Schotten-Baumann reaction and mixed anhydride method to give the compounds of this invention represented by the formula [I].
(C) The compounds of this invention represented by the formula [VI] are synthesized by the following method. ##STR8## The compounds represented by the formula
R.sup.9 --Y [VII]
wherein Y is halogen; are reacted with the compounds represented by the formula ##STR9## by a known method to give the compounds of this invention represented by the formula [VI].
The compounds of the formula [I] synthesized by the above methods can form the conventional salts to be generally used as medicine such as sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, diethylamine salt, triethanolamine salt, etc.
The compounds of the formula [I] have the stereoisomers which are within the limit of this invention, because they have one or more asymmetric carbon atoms.
Examples are shown below, although this invention is not limited to these examples.
2.2 g of (4R)-3-[(2S)-2-mercaptopropanoyl]-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 50 ml of water. To this solution, 1.6 g of p-toluoyl chloride is added dropwise with stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and at room temperature for additional 1 hour. The reaction solution is washed with ethyl acetate, and acidified with conc. hydrochloric acid to give crystals. The crystals (the titled compound) are collected by filtration, yield 3.3 g (97%), mp. 166°-166.5° C. (ethyl acetate), [α]D 25 -148.6°(c=1.1, methanol).
IR (nujol, cm-1) 1766, 1650, 1620, 1605, 1428, 1215, 1208, 1174, 913.
NMR (CDCl3, δ) 1.60 (3H, d, J=7 Hz), 2.40 (3H, s), 3.30 (2H, d, J=5 Hz), 4.63 (1H, q, J=7 Hz), 4.64, 4.93 (2H, ABq, J=7.5 Hz), 5.10 (1H, t, J=5 Hz), 7.22, 7.82 (4H, A2 B2, each d, J=8 Hz), 10.46 (1H, s).
Analysis (C15 H17 NO4 S2) Calcd: C, 53.08; H, 5.05; N, 4.13. Found: C, 52.98; H, 5.00; N, 4.10.
2.4 g of (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 50 ml of water. To this solution, 1.8 g of cyclohexanecarbonyl chloride is added dropwise with stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and at room temperature for additional 1 hour. This reaction solution is washed with ethyl acetate, acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 3.5 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 2.8 g (81%), mp. 78.5°-80° C. (benzene-n-hexane), [α]D 23 -176.2° (C=1.0, methanol).
IR (nujol, cm-1) 1737, 1694, 1602, 1439, 1198, 972.
NMR (CHCl3, δ) 1.25 (3H, d, J=6 Hz), 1.30-2.20 (10H, m), 2.50 (1H, m), 2.70-310 (3H, m), 3.32 (2H, d, J=5 Hz), 4.50, 4.77 (2H, ABq, J=8 Hz), 5.10 (1H, t, J=5 Hz), 10.20 (1H, s).
Analysis (C15 H23 NO4 S2) Calcd: C, 52.15; H, 6.71; N, 4.05. Found: C, 52.16; H, 6.66; N, 3.81.
2.7 g of (4R)-2-(2-acetoxyphenyl)-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 60 ml of water. To this solution, 1.8 g of S-acetyl-3-mercaptopropanoyl chloride is added dropwise with stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and at room temperature for additional 1 hour. The reaction solution is washed with ethyl acetate, and acidified with conc. hydrochloric acid to give crystals. The crystals (the titled compound) are collected by filtration, yield 2.8 g (70%), mp. 144°-145° C. (ethyl acetate-benzene), [α]D 27 +109.0° (c=1.0, methanol).
IR (nujol, cm-1) 1770, 1738, 1691, 1605, 1169, 907.
NMR (CDCl3, δ) 2.27 (3H, s), 2.37 (3H, s), 2.10-2.80 (2H, m), 3.08 (2H, d.d, J=5.5, 6 Hz), 3.30 (2H, d, J=7.3 Hz), 4.97 (1H, t, J=7.3 Hz), 6.20 (1H, s), 7.00-7.50 (3H, m), 7.98 (1H, m), 10.18 (1H, s).
Analysis (C17 H19 NO6 S2) Calcd: C, 51.37; H, 4.82; N, 3.52. Found: C. 51.58; H. 4.75; N, 3.50.
2.7 g of (4R)-2-(2-acetoxyphenyl)-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 60 ml of water. To this solution, 2.6 g of S-(4-methylbenzoyl)-3-mercaptopropanoyl chloride is added dropwise with stirring under icecooling. After the addition, the mixture is stirred under icecooling for 1 hour and at room temperature for additional 1 hour. This reaction solution is washed with ethyl acetate, acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 3.6 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 2.7 g (57%), mp. 93°-96° C. (benzene). [α]D 24 +80.4° (c=1.0, methanol).
IR (nujol, cm-1) 3560, 1768, 1721, 1635, 1204, 1178, 918.
NMR (CDCl3, δ) 2.30 (3H, s), 2.38 (3H, s), 2.63 (2H, m), 3.10-3.50 (4H, m), 4.97 (1H, t, J=7.5 Hz), 5.61 (2H, br. s), 6.19 (1H, s), 6.90-8.20 (8H, m).
Analysis (C23 H23 NO6 S2.1/2H2 O) Calcd: C, 57.25; H, 5.01; N, 2.90. Found: C, 57.51; H, 5.07; N, 2.62.
1.8 g of 4-acetylaminobenzoic acid is dissolved in 20 ml of dry tetrahydrofuran. To this solution, 1.4 ml of triethylamine is added. To this mixture, 1.3 ml of isobutyl chloroformate is added dropwise with stirring at -5° C. After ten minutes, to this solution, 20 ml of aqueous solution of 2.4 g of (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid and 1.4 ml of triethylamine is added, and the mixture is stirred at room temperature for 30 min. To this reaction solution, 40 ml of water is added, and the obtained mixture is washed with ethyl acetate. The aqueous layer is acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 4.1 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 3.6 g (90%), mp. 206°-207° C. (methanol), [α]D 27 -152.5° (c=1.0methanol).
IR (nujol, cm-1) 3286, 1735, 1645, 1622, 1585, 1524, 1455, 1318, 1210, 1170, 913.
NMR (DMSO-d6, δ) 1.18 (3H, d, J=6 Hz), 2.10 (3H, s), 2.70-3.50 (5H, m), 4.57, 4.88 (2H, ABq, J=9 Hz), 4.94 (1H, d.d, J=6,3 Hz), 7.73, 7.87 (4H, A2 B2, each d, J=9 Hz), 10.30 (1H, s).
Analysis (C17 H20 N2 O5 S2) Calcd: C, 51.50; H, 5.08; N, 7.07. Found: C, 51.32; H, 5.06; N, 7.02.
Under a nitrogen atmosphere, to the solution of 3.4 g of (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid in 11 ml of dry N,N-dimethylformamide, 1.4 ml of triethylamine and 1.5 g of chloromethyl pivalate are added, and stirred at 90° C. for 6 hours. The reaction mixture is poured into 100 ml of ice-water, and extracted with ether. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 4.8 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 4.1 g (91%), mp. 69°-69.5° C. (benzene-n-hexane), [α]D 25 -153.8° (c=1.0, methanol).
IR (nujol, cm-1) 1770, 1751, 1655, 1643, 1457, 1417, 1204, 1102, 990, 912.
NMR (CDCl3, δ) 1.18 (9H, s), 1.30 (3H, d, J=6 Hz), 2.93 (1H, m), 3.17 (4H, m), 4.50, 4.77 (2H, ABq, J=8 Hz), 5.13 (1H, d.d, J=5, 6 Hz), 5.70, 5.80 (2H, ABq, J=6 Hz), 7.20-8.07 (5H, m).
Analysis (C21 H27 NO6 S2) Calcd: C, 55.61; H, 6.00; N, 3.09. Found: C, 55.73; H, 5.98; N, 2.97.
Tables I to VIII show various compounds and physical constants including the compounds specified in the examples.
TABLE I
__________________________________________________________________________
##STR10##
Method
of
prepn.
Compd. (Examp.
Yield Recrystn.
[α].sub.D
IRg.
No. R R.sup.2 No.) (%) mp. (°C.)
solvent
(c, solv., °C.)
(nujol,
__________________________________________________________________________
cm.sup.-1)
1 H COCMe.sub.3
3 91 195-196
EtOAc -- 3180, 1719, 1676,
1616,
benzene 1596, 1448, 1247
2 Me (S config.)
##STR11##
1 94 183-184
EtOAc benzene
-10.9 (1.0, MeOH,
3330, 1714, 1663,
1621, 1602, 1462, 910
3 H
##STR12##
2* 80 oil +42.5 (0.5, MeOH,
1723, 1645, 1605,
1175, 913, 826
(CHCl.sub.3,
__________________________________________________________________________
cm.sup.-1)
*Starting material, thiol: mp. 197-198° C. (dec.) (EtOAcchexane),
[α].sub.D.sup.25 +34.7° (c = 0.5, MeOH), IR (nujol,
cm.sup.-1) 3360, 1720, 1685, 1605, 1585, 1280, 1165, 760.
TABLE II
__________________________________________________________________________
##STR13##
Method
of
prepn.
Compd. (Examp.
Yield Recrystn.
[α].sub.D deg.
IR
No. R.sup.4
No.) (%) mp. (°C.)
solvent
(c, solv., °C.)
(nujol, cm.sup.-1)
__________________________________________________________________________
4 * 5 63 42-45 -107.3 1723, 1665, 1635, 1590,
(0.9, CHCl.sub.3, 25)
1290, 1075 (CHCl.sub.3, cm.sup.-1)
5 **
5 74 121-124 -120.2 3320, 3240, 1725, 1625,
(1.2, MeOH, 25)
1595, 1560, 1382, 1340,
1176, 1160
__________________________________________________________________________
##STR14##
##STR15##
TABLE III
__________________________________________________________________________
##STR16##
Method
of
prepn.
Compd. (Examp.
Yield Recrystn.
[α].sub.D
IRg.
No. R.sup.8 R.sup.5
No.) (%) mp. (°C.)
solvent
(c, solv., °C.)
(nujol,
__________________________________________________________________________
cm.sup.-1)
6 Me H 2 84 126-127
EtOAc
-156.0 1722, 1605, 1344,
1264,
(1.1, MeOH, 26)
1201
7 CH.sub.2 Ph
H 1 92 98.5-99.5
benzene 1762, 1610, 1346,
1209,
1175, 835, 807
8 COC.sub.17 H.sub.31 **
H 2 74 oil -202.1 1745, 1690, 1635,
1460,
(0.5, CHCl.sub. 3,
1380, 1095 (neat,
cm.sup.-1)
9
##STR17## H 2 81 79.5-80
benzene- n-hexane
-176.2 (1.0, MeOH,
1737, 1694, 1602,
1439, 1198, 972
10
##STR18## H 1 87 189-190.5*
MeOH -114.8* (1.0, MeOH,
1685, 1635, 1555,
1380, 900, 780*
11 COCH.sub.2 Ph
H 1 71 131-131.5
MeOH -162.2 1735, 1682, 1600,
1200,
(1.3, MeOH, 24)
1010, 710
12a
##STR19## H 2 35 118-118.5
(i-Pr).sub.2 O
-70.9 (0.9, MeOH,
1740, 1680, 1620,
1390, 1210, 920
12b
##STR20## H 2 38 oil -107.5 (1.1, MeOH,
1750, 1680, 1620,
1390, 1210, 950
(neat, cm.sup.-1)
13 *** H 5 58 43- 46 -100.0 1725, 1660, 1588,
1290,
(0.4, CHCl.sub.3,
1074 (CHCl.sub.3,
cm.sup.-1)
14 **** H 5 63 122-125 -125.6 3320, 3240, 1725,
1623,
(1.1, MeOH, 25)
1594, 1555, 1377,
1305,
1182, 1156
15
##STR21##
##STR22##
2 80 oil -114.5 (1.0, MeOH,
1728, 1680, 1640,
1418, 973
(CHCl.sub.3,
cm.sup.-1)
16 CO.sub.2 CH.sub.2 Ph
##STR23##
2 91 oil -87.3 (1.0, MeOH,
1737, 1705, 1642,
1414, 1237, 1146
(neat, cm.sup.-1)
17 CO.sub.2 CH.sub.2 Ph
##STR24##
2 83 oil +31.5 (1.0, MeOH,
1738, 1704, 1653,
1415, 1237, 1142
(neat, cm.sup.-1)
18
CH.sub.2 CO.sub.2 H
##STR25##
1 59 132-134
MeOH EtOAc 1725,
__________________________________________________________________________
1630
*Dicyclohexylamine salt.
**COC.sub.17 H.sub.31 is linoloyl.
##STR26##
##STR27##
TABLE IV
__________________________________________________________________________
##STR28##
Method
of
prepn.
Compd. (Examp.
Yield Recrystn.
[α].sub.D
IRg.
No. R.sup.5 R.sup.11 n No.) (%) mp. (°C.)
solvent
(c, solv., °C.)
(nujol,
__________________________________________________________________________
cm.sup.-1)
19 H 4-Me 0 1 97 166-166.5
EtOAc
-148.6 1766, 1650, 1620,
(1.1, MeOH,
1605, 1428, 1215,
1208, 1174, 913
20 H 2-Me 1 1 79 101-103
benzene-
-175.6 3080, 1761, 1660,
n-hexane
(1.0, MeOH,
1614, 1215, 1200,
910, 770
21 H 3-Me 1 1 85 113-115
benzene-
-145.2 3080, 1750, 1652,
n-hexane
(1.0, MeOH,
1612, 1150, 808
22 H 4-Me 1 1 91 142-142.5
benzene
-171.9 1755, 1646, 1607,
(1.0, MeOH,
1460, 1206, 1176,
916
23 H 4-Pri 1 1 76 143-145
benzene
-161.2 1738, 1653, 1607,
(1.0, MeOH,
1179, 921
24 H 3,4-Me.sub.2
1 1 90 138-138.5
benzene
-165.6 1755, 1654, 1610,
(1.0, MeOH,
1440, 830
25 H 3,5-Me.sub.2
1 1 96 140-142
benzene
-172.9 1734, 1648, 1610,
(1.0, MeOH,
1289, 1218, 1154
26 H 2-OAc 1 5 53 117-119
benzene
-163.2 3140, 1771, 1755,
(1.0, MeOH,
1652, 1625, 1185,
931, 907
27 H 4-NHAc 1 5 90 206-207
MeOH -152.5 3286, 1735, 1645,
(1.0, MeOH,
1622, 1585, 1524,
1455, 1318, 1210,
1170, 913
28 H
##STR29##
1 2 80 62-64 -185.4 (1.2, MeOH,
3280, 1740, 1620,
1600, 1575, 1190,
1162, 1120, 905
147.5-
acetone-
149* MeOH
ether
29
##STR30##
3,4,5-(OMe).sub.3
1 2 60 oil -78.0 (1.1, MeOH,
1741, 1652, 1586,
1325, 1232, 1129,
1003 (neat,
cm.sup.-1)
__________________________________________________________________________
*Dicyclohexylamine salt.
TABLE V.
__________________________________________________________________________
##STR31##
Method
of
prepn.
Compd. (Examp.
Yield Recrystn.
[α].sub.D
IRg.
No. R.sup.12
R.sup.13
R No.) (%) mp. (°C.)
solvent
(c, solv., °C.)
(nujol,
__________________________________________________________________________
cm.sup.-1)
30 Me 2-OH
H 4 45 74-76.5*
AcOEt +135.9* 3160, 1740, 1610, 1590,
ether (1.0, MeOH, 26)
1455, 1380*
31 Me 2-OMe
H 4 74 75-76.5
benzene
+129.3 1760, 1600, 1380, 1240,
(1.0, MeOH, 24)
1030, 775
32 Ac 2-OAc
H 3 70 144-145
EtOAc +109.0 1770, 1738, 1691, 1605,
benzene
(1.0, MeOH, 27)
1169, 907
33 COEt 2-OH
H 3 54 89-92
EtOAc +156.4 3250, 2650, 1740, 1645,
benzene
(1.0, MeOH, 26)
1610, 1234, 925
34 CO(CH.sub.2).sub.6 Me
2-OH
H 2 39 oil +137.4 3260, 1726, 1654, 1411,
(1.0, MeOH, 23)
1284, 1220, 1044
(CHCl.sub.3,
cm.sup.-1)
35 COCMe.sub.3
2-OH
H 1 89 155-156
EtOAc +140.9 3240, 1740, 1684, 1621,
(dec.)
benzene
(1.0, MeOH, 27)
1388, 938
36 COCMe.sub.3
4-OMe
Me 1 73 140-141
benzene
+73.9 1723, 1663, 1610, 964
(1.0, MeOH, 26)
37 COCMe.sub.3
2-OH,
H 3 82 147-148
EtOAc +142.8 3290, 1710, 1693, 1270,
3-OMe benzene
(1.0, MeOH, 28)
1063, 932
38 COCH.sub.2 Ph
2-OH
H 2 85 57-59 +120.9 1724, 1680, 1650, 1602,
(1.0, MeOH, 25)
1403, (CHCl.sub.3,
cm.sup.-1)
39 COCH.sub.2 Ph
2-OAc
H 2 63 oil +72.0 1763, 1727, 1653, 1637,
(0.8, MeOH, 24)
1605, 1400, 1198 (neat,
cm.sup.-1)
40
##STR32##
2-OH
H 1 62 201-202 (dec.)
+157.2 (1.0, MeOH,
3360, 1730, 1675, 1635,
1600, 925
41
##STR33##
2-OH, 5-Cl
Me 1 54 205-206 (dec.)
MeOH EtOAc benzene
+105.5 (0.5, MeOH,
3190, 1729, 1672, 1623,
1278, 1229, 916
42 CO.sub.2 CH.sub.2 Ph
2-OH
H 2 96 oil +121.5 3290, 1707, 1629, 1142
(1.0, MeOH, 27)
(neat, cm.sup.-1)
43 CH.sub.2 CO.sub.2 H
H H 2 62 oil +97.9 1720, 1650, 1400
(CHCl.sub.3,
(1.0, MeOH, 27)
cm.sup.-1)
44 CH.sub.2 CO.sub.2 H
2-OH
H 1 86 158-159
MeOH +144.8 3310, 1715, 1626, 1247,
(dec.)
EtOAc (1.0, MeOH, 27)
1211, 934
__________________________________________________________________________
*This crystal contains an equimolar ether as crystalline solvent.
TABLE VI.
__________________________________________________________________________
##STR34##
Method
of
prepn.
Compd. (Examp.
Yield Recrystn.
[α].sub.D
IRg.
No. R.sup.14
R.sup.15
R n No.) (%) mp. (°C.)
solvent
(c, solv.,
(nujol,
__________________________________________________________________________
cm.sup.-1)
45 4-Me 2-OH H 0 2 72 86-113 +124.0 3300, 1723,
(dec.) (1.0, MeOH,
1635, 1217,
1176, 913
46 4-Me 2-OH H 1 4 93 100-105 +128.8 3200, 1735,
(dec.) (1.1, MeOH,
1650, 1630,
1600, 1170,
910
47 4-Me 2-OAc H 1 4 57 93-96 benzene
+80.4 3560, 1768,
(1.0, MeOH,
1721, 1635,
1204, 1178,
918
48 4-Me 2-OH, 4-OMe
H 1 4 69 oil 1730, 1650,
1610, 1400,
1250, 1230,
1100, 910
(CHCl.sub.3,
cm.sup.-1)
49 4-Me 2-OH, 4-OME
Me 1 2 80 106-107.5
EtOAc 3360, 3160,
(i-Pr).sub.2 O 1720, 1650,
1615, 1210,
1180, 915
50 4-Me 2-OAc, 4-OMe
H 1 4 80 oil *
51 4-Cl 2-OH Me 1 2 86 65-79 +109.1 3200, 1726,
(1.0, MeOH,
1660, 1625,
1205, 1092,
916
52 4-Cl 2-NO.sub.2
Me 1 2 73 oil -232.5 1730, 1659, 919
(0.8, MeOH,
(CHCl.sub.3,
cm.sup.-1)
53 4-OH 2-OH H 1 2 88 133-134
EtOAc +124.8 3460, 3330,
(dec.)
benzene
(1.0, MeOH,
1720, 1652,
1580, 1207,
1166, 911,
847, 768
54 4-OCH.sub.2 Ph
2-OH H 1 2 47 125.5-128.5
EtOH +108.5 3480, 3412,
H.sub.2 O
(1.0, MeOH,
1710, 1624,
1605, 1572,
1261, 1246,
1220, 1208,
1168, 920,
838, 761, 742
55 4-OMe 4-Me H 1 3 67 121-129
EtOAc +115.0 1720, 1637,
ether (0.5, MeOH,
1620, 1607,
926
56 4-OMe 2-OH H 1 3 80 160-161
MeOH +137.8 3260, 1736,
(dec.)
EtOAc (1.0, MeOH,
1653, 1598,
benzene 1247, 1171, 916
57 4-OMe 2-OMe H 1 1 76 166.5-167.5
EtOAc +139.3 1734, 1637,
benzene
(1.1, MeOH,
1603, 913
58 3,4,5-(OMe).sub.3
2-OH H 1 4 69 97- 101 +116.1 3200, 1730,
(1.2, MeOH,
1650, 1620,
1580, 1140,
1120, 820
59 3,4,5-(OMe).sub.3
3,4,5-(OMe).sub.3
Me 1 2 68 65-72 +111.0 1750, 1720,
(1.2, MeOH,
1650, 1630,
1590, 1320,
1125, 1000
(CHCl.sub.3,
cm.sup.31 1)
60 4-OAc 2-OAc H 1 5 66 72-76 +67.6 1755, 1650,
(0.7, MeOH,
1600, 1190˜
1200, 1160, 913
61 4-NHAc 2-OH H 1 5 67 92.5-94 +100.6 3280, 1715,
(dec.) (1.0, MeOH,
1650, 1630,
1590, 1210,
1170, 912
62 4-NHAc 3,4-OCH.sub.2 O
Me 1 5 85 82-84 +112.4 3280, 1740,
(1.0, MeOH,
1653, 1625,
1593, 1520,
1460, 915
63 4-NHAc 4-NHAc Me 1 5 55 oil +144.6 3280, 1710,
(0.9, MeOH,
1650, 1635,
1599, 916
(neat,
__________________________________________________________________________
cm.sup.-1)
*NMR (CDCl.sub.3, δ) 2.40 (3H, s), 2.43 (3H, s), 2.53-3.50 (6H, m),
3.73 (3H, s), 4.97 (1H, t, J = 6Hz), 6.20 (1H, s), 6.78 (1H, s), 7.00-7.4
(2H, m), 7.75, 8.03 (4H, A.sub.2 B.sub.2, each d, J = 8Hz), 8.43 (1H,
br.s).
TABLE VII.
__________________________________________________________________________
##STR35##
Method
of
prepn. [α].sub.D deg.
Compd. (Examp.
Yield Recrystn.
(c, solv.,
IR
No. Q R.sup.9 R.sup.10
R.sup.5
R No.) (%) mp. (°C.)
solvent
°C.)
(nujol,
__________________________________________________________________________
cm.sup.-1)
64 S CH.sub.2 OCOCMe.sub.3
COPh
H Me 6 91 69-69.5
benzene-
-153.8
1770, 1751
n-hexane
(1.0, 1655, 1643,
MeOH,
1457, 1417,
1204, 1102,
990, 912
65 S
##STR36## COPh
H Me 6 88 oil -106.9 (1.3, MeOH,
1757, 1740, 1662,
1652, 1416, 1207,
070, 915 (neat,
cm.sup.-1)
66 S
##STR37## COPh
H Me 6 90 62-64 -89.7 (0.7, MeOH,
1784, 1755, 1725,
1650, 1456, 1408,
379, 1205, 915,
728
67
S
##STR38## COPh
H Me 6 92 99-100
ether
-131.6 (0,9, MeOH,
1772, 1739, 1707,
1652, 1628, 1460,
170, 910, 729
68 S CH.sub.2 OCOCMe.sub.3
Ac
##STR39##
H 6 82 oil +83.0 (0.7, MeOH,
1767, 1680, 1657,
1404, 1172, 1111,
94 (CHCl.sub.3,
cm.sup.-1)
__________________________________________________________________________
TABLE VIII
______________________________________
Elementary Analysis
Analysis (%)
Calcd.
(Found)
Compd. .THorizBrace.
No. Formula C H N
______________________________________
9 C.sub.15 H.sub.23 NO.sub.4 S.sub.2
52.15 6.71 4.05
(52.16) (6.66)
(3.81)
11 C.sub.16 H.sub.19 NO.sub.4 S.sub.2
54.37 5.42 3.96
(54.28) (5.38)
(3.95)
19 C.sub.15 H.sub.17 NO.sub.4 S.sub.2
53.08 5.05 4.13
(52.98) (5.00)
(4.10)
20 C.sub.16 H.sub.19 NO.sub.4 S.sub.2
54.37 5.42 3.96
(54.24) (5.36)
(4.02)
21 C.sub.16 H.sub.19 NO.sub.4 S.sub.2
54.37 5.42 3.96
(54.19) (5.36)
(4.03)
22 C.sub.16 H.sub.19 NO.sub.4 S.sub.2
54.37 5.42 3.96
(54.55) (5.38)
(3.94)
23 C.sub.18 H.sub.23 NO.sub.4 S.sub.2
56.67 6.08 3.67
(57.04) (6.08)
(3.57)
24 C.sub.17 H.sub.21 NO.sub.4 S.sub.2
55.56 5.76 3.81
(55.77) (5.73)
(3.58)
25 C.sub.17 H.sub.21 NO.sub.4 S.sub.2
55.56 5.76 3.81
(55.74) (5.75)
(3.74)
26 C.sub.17 H.sub.19 NO.sub.6 S.sub. 2
51.37 4.82 3.52
(51.71) (4.80)
(3.37)
27 C.sub.17 H.sub.20 N.sub.2 O.sub.5 S.sub.2
51.50 5.08 7.07
(51.32) (5.06)
(7.02)
32 C.sub.17 H.sub.19 NO.sub.6 S.sub.2
51.37 4.82 3.52
(51.58) (4.75)
(3.50)
35 C.sub.18 H.sub.23 NO.sub.4 S.sub.2
56.67 6.08 3.67
(56.10) (5.83)
(3.43)
37 C.sub.19 H.sub.25 NO.sub.6 S.sub.2
53.38 5.89 3.28
(53.54) (5.86)
(3.29)
40 C.sub.19 H.sub.18 N.sub.2 O.sub.5 S.sub.2 · 1/2H.sub.2
53.38 4.48 6.55
(53.65) (4.32)
(6.48)
41 C.sub.20 H.sub.19 ClN.sub.2 O.sub.5 S.sub.2
51.44 4.10 6.00
(51.10) (4.05)
(5.88)
44 C.sub.15 H.sub.17 NO.sub.6 S.sub.2
48.51 4.61 3.77
(48.51) (4.60)
(3.74)
46 C.sub.21 H.sub.21 NO.sub.5 S.sub.2
58.45 4.90 3.25
(58.58) (5.01)
(3.21)
47 C.sub.23 H.sub.23 NO.sub.6 S.sub.2 · 1/2H.sub.2 O
57.25 5.01 2.90
(57.51) (5.07)
(2.62)
56 C.sub.21 H.sub.21 NO.sub.6 S.sub.2
56.36 4.73 3.13
(56.53) (4.74)
(3.12)
58 C.sub.23 H.sub.25 NO.sub.8 S.sub.2
54.42 4.96 2.76
(54.17) (4.99)
(2.73)
64 C.sub.21 H.sub.27 NO.sub.6 S.sub.2
55.61 6.00 3.09
(55.73) (5.98)
(2.97)
66 C.sub.24 H.sub.22 N.sub.2 O.sub.6 S.sub.2 · 1/6C.sub.6
H.sub.6 58.69 4.53 5.48
(58.66) (4.41)
(5.82)
67 C.sub.25 H.sub.24 N.sub.2 O.sub.6 S.sub.2
58.58 4.72 5.47
(58.70) (4.64)
(5.41)
______________________________________
Table IX shows the results of the pharmacological tests when the represented compounds of the compounds [I] of this invention and the related salts are used as antihypertensive agents. Table IX clearly shows that the compounds of this invention have the long-lasting, useful antihypertensive effect, and stability is also excellent.
As recently it has been clear that the compounds inhibiting angiotensin I-converting enzyme may be the curative potency against both renal hypertension and essential hypertension, the compounds of this invention are evaluated as antihypertensive agents by the following method.
Male Wistar strain rats weighing 200-300 g were used. Under ether anesthesia, polyethylene cannulae are inserted into carotid artery and jugular vein. The cannula to carotid artery is connected to an electric transducer, while the cannula to jugular vein is connected to an apparatus for continuous infusion. After the complete recovery from anesthesia, angiotensin I is infused intravenously in a dose of 300 ng/kg by the apparatus for continuous infusion, and the pressor response is recorded by polygraph (Nihon Koden, RM-150). The compounds of this invention suspended in 0.5% tragacanth solution are administered orally in a dose of 0.3 ml per 100 g of body weight, and the pressor response to angiotensin I infused intravenously is measured with time. The inhibitory activity of the compounds against angiotensin I-converting enzyme is expressed as the percent inhibition of pressor response to angiotensin I. Table IX shows the changes of percent inhibition of the compounds of this invention with time.
The compounds of this invention as well as the known antihypertensive mercaptoacylamino acids suppress the pressor response to angiotensin I by administered orally to unanesthesized rats, the mechanism of which is derived from inhibiting angiotensin I-converting enzyme. The compounds of this invention are derivatives of mercaptoacylamino acid, and with the comparative result in the suppressive effect of pressor response to angiotensin I by administering these equimolar compounds orally it has been proved that the compounds of this invention are well absorbed from the gastroenteric wall, and hydrolyzed gradually at the part to be shown the activity so that they have the advantages as antihypertensive agent such as durability.
The stability of mercaptoacylamino acids is compared with that of ester derivatives or S-acyl and S-alkyl derivatives in the ethanol or the phosphate buffer solution (pH 7.0).
Condition for preservation: at room temperature, for 1 month.
Result: Ester derivatives and S-acyl and S-alkyl derivatives are more stable than mercaptoacylamino acids.
The value of acute toxicity of (4R)-2-(2-acetoxyphenyl)-3-(S-acetyl-3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid (Compound 32) is LD>500 mg/kg.
The male ddy-std. strain mice (4 weeks of age, weighing 19-21 g) were placed in a breeding room of constant temperature and humidity (23±1° C., 55±5%) and fed freely pellet diet (CE-2, Clea Japan, Inc.) and water ad. libitum for a week. The mice showing the normal growth were selected for the experiment.
Test compound is suspended in 0.5% tragacanth solution, and administered intraperitoneally in a dose of 0.5 ml per 20 g B.W.
TABLE IX.
__________________________________________________________________________
Compd.
Dose Inhibition (%)
No. (mg/kg)
5 15 25 35 45 55 65 75 85 95 105
115 (min.)
__________________________________________________________________________
2 1.8 39.3
58.1
64.0
60.0
73.0
57.2
55.0
54.5
42.0
39.5
42.0
37.0
2A 1.3 20.0
40.0
37.5
36.5
33.7
30.0
28.2
20.0
30.0
24.8
21.0
20.0
2B 1.8 7.9
36.8
36.8
36.8
45.7
31.6
31.6
31.6
21.1
21.1
15.8
15.8
22 1.5 45.2
60.4
51.4
59.0
55.0
50.8
55.0
53.5
49.4
46.5
39.8
31.6
22A 1.0 34.0
51.5
49.7
45.0
37.5
30.2
30.2
30.2
28.0
19.8
10.2
8.0
22B 1.4 45.4
60.7
60.6
45.4
45.4
45.4
42.4
36.4
30.3
21.2
21.2
21.2
32 1.7 40.2
55.3
70.2
70.2
61.1
54.2
55.3
57.2
48.2
43.4
27.3
32C 1.3 53.3
62.9
64.7
63.7
54.0
49.3
47.7
38.8
34.0
30.0
30.0
31.0
64 1.9 30.0
59.5
69.5
59.9
55.7
53.5
47.1
37.2
36.5
30.8
27.8
24.5
__________________________________________________________________________
A. Corresponding thiol compounds.
B. Corresponding S--benzoyl compounds.
C. Corresponding thiol and phenolic hydroxy compound.
It is found from the above pharmacological tests that the compounds [I] to [V] of this invention are useful as antihypertensive agents having the lasting property. The compounds can be given with the combination of diuretics such as hydroflumethiazide, furosemide, and bumetanide same as other antihypertensive agents. The compounds can be administered either orally or parenterally. The dosage forms are tablet, capsule, granule, powder, suppository, injection, etc. In the treatment of hypertension, these preparations can contain not only general excipients but also other antihypertensive agents such as reserpine, α-methyldopa, guanethidine, clonidine, hydralazine, etc. The dose is adjusted depending on symptom, dosage form, etc. But, usual daily dosage is 1 to 5000 mg, preferably 10 to 1000 mg, in one or a few divided doses.
______________________________________
(a) tablet
compound 2 30 mg
lactose 150 mg
crystalline cellulose 50 mg
calcium carboxymethylcellulose
7 mg
magnesium stearate 3 mg
total 240 mg
compound 22 30 mg
lactose 150 mg
crystalline cellulose 50 mg
calcium carboxymethylcellulose
7 mg
magnesium stearate 3 mg
total 240 mg
compound 9 150 mg
lactose 60 mg
crystalline cellulose 30 mg
calcium carboxymethylcellulose
7 mg
magnesium stearate 3 mg
total 250 mg
compound 32 150 mg
lactose 60 mg
crystalline cellulose 30 mg
calcium carboxymethylcellulose
7 mg
magnesium stearate 3 mg
total 250 mg
______________________________________
The tablets may be treated with common film-coating and further with sugar-coating.
______________________________________
(b) granule
compound 53 30 mg
polyvinylpyrrolidone 25 mg
lactose 385 mg
hydroxypropylcellulose 50 mg
talc 10 mg
total 500 mg
compound 22 30 mg
polyvinylpyrrolidone 25 mg
lactose 385 mg
hydroxypropylcellulose 50 mg
talc 10 mg
total 500 mg
(c) powder
compound 64 30 mg
lactose 500 mg
starch 440 mg
colloidal silica 30 mg
total 1000 mg
compound 22 30 mg
lactose 500 mg
starch 440 mg
colloidal silica 30 mg
total 1000 mg
compound 9 300 mg
lactose 230 mg
starch 440 mg
colloidal silica 30 mg
total 1000 mg
compound 32 300 mg
lactose 230 mg
starch 440 mg
colloidal silica 30 mg
total 1000 mg
(d) capsule
compound 2 30 mg
lactose 102 mg
crystalline cellulose 56 mg
colloidal silica 2 mg
total 190 mg
compound 22 30 mg
lactose 102 mg
crystalline cellulose 56 mg
colloidal silica 2 mg
total 190 mg
compound 53 30 mg
glycerol 349.98 mg
butyl p-hydroxybenzoate
0.02 mg
total 380 mg
compound 64 30 mg
glycerol 349.98 mg
butyl p-hydroxybenzoate
0.02 mg
total 380 mg
______________________________________
1 to 30 mg of compound 2 is contained in 1 ml of the aqueous solution (pH 6.5-7.0).
Claims (17)
1. A compound of the formula ##STR40## wherein Q is sulfur;
Ra is R1 or R9 ;
Rb is R6, R8 or R10 ; and
Rc is R5 or R7 ;
and
when Rb is R8, Rc is R5 ;
when Rb is R6, Rc is R7 ;
when Rb is R10, Rc is R5, and Ra is R9 ;
R1 is hydrogen;
R5 is cyclohexyl, phenyl, furyl, thienyl, pyridyl, naphthyl, substituted cyclohexyl, substituted phenyl, substituted furyl, substituted thienyl, substituted pyridyl or substituted naphthyl wherein the substitutent(s) is lower alkyl, hydroxy, lower alkoxy, acyloxy, mercapto, acylmercapto, halogen, nitro, amino, lower alkylamino, acylamino, lower alkylenedioxy or carboxy;
R6 is acetyl;
R7 is cyclohexyl, furyl, thienyl, pyridyl, naphthyl or substituted phenyl wherein the substituent(s) is acyloxy, mercapto, acylmercapto, amino, lower alkylamino, acylamino, lower alkylenedioxy or carboxy;
R8 is lower alkyl, lower alkanoyl except acetyl, higher alkanoyl, cyclohexanecarbonyl, aralkyl, phenyl-lower alkanoyl, pyridylcarbonyl, benzyloxycarbonyl, naphthoyl, substituted lower alkyl, substituted benzoyl, or substituted phenyl-lower alkanoyl wherein the substituent(s) is lower alkyl, lower alkoxy, hydroxy, phenyl-lower alkoxy, acyloxy, halogen, mercapto, acylmercapto, nitro, amino, lower alkylamino, arylamino, acylamino or carboxy;
R9 is phenyl, alkoxy-lower alkyl, acyloxy-lower alkyl, imido-lower alkyl or substituted phenyl wherein the substituent(s) is lower alkyl, lower alkoxy, hydroxy, acyl, acyloxy, halogen, nitro, amino, lower alkylamino, acylamino or carboxy;
R10 is lower alkyl, lower alkanoyl, higher alkanoyl, cyclohexanecarbonyl, aralkyl, benzoyl, phenyl-lower alkanoyl, pyridylcarbonyl, benzyloxycarbonyl, naphthoyl, substituted lower alkyl, substituted benzoyl or substituted phenyl-lower alkanoyl wherein the substituent(s) is lower alkyl, lower alkoxy, hydroxy, phenyl-lower alkoxy, acyloxy, halogen, mercapto, acylmercapto, nitro, amino, lower alkylamino, acylamino or carboxy; and
wherein in the groups defined herein lower alkyl groups contain 1 to 6 carbon atoms, higher alkyl groups contain 7 to 20 carbon atoms, alkyl groups contain 1 to 20 carbon atoms, aralkyl groups are phenyl-lower alkyl groups, acyloxy groups are lower alkanoxy, benzoyloxy, or benzyloxycarbonyloxy groups, acylamino groups are lower alkanoylamino, benzoylamino, or benzyloxycarbonylamino groups, acylmercapto groups are lower alkanoylmercapto or benzoylmercapto groups, arylamino groups are phenylamino or phenylamino groups substituted with lower alkyl or lower halogenalkyl groups, and acyl groups are acetyl or benzoyl groups; and
Z is straight or branched alkylene with 1 to 3 carbon atoms; and salts thereof.
2. A compound as in claim 1 wherein Z is --CH2 --, --CH(CH3)--, --CH2 CH2 -- or --CH(CH3)CH2 --.
3. A compound as in claim 1 wherein Ra is R1, Rb is R6 and Rc is R7.
4. A compound as in claim 3 wherein R7 is 2-acetoxyphenyl.
5. A compound as in claim 1 wherein Ra is R1, Rb is R8 and Rc is R5.
6. A compound as in claim 5 wherein R5 is cyclohexyl, phenyl, 2-furyl, 4-pyridyl, 4-methylphenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3,4,5-trimethoxyphenyl, 2-acetoxyphenyl, 2-hydroxy-3-methoxyphenyl, 2-hydroxy-4-methoxyphenyl, 5-chloro-2-hydroxyphenyl, 2-acetoxy-4-methoxyphenyl, 2-nitrophenyl, 4-acetylaminophenyl or 3,4-methylenedioxyphenyl.
7. A compound as in claim 5 wherein R8 is methyl, propionyl, pivaloyl, octanoyl, linoloyl, cyclohexanecarbonyl, benzyl, phenylacetyl, 2-(4-isobutylphenyl)propionyl, 3-pyridylcarbonyl, benzyloxycarbonyl, 1-naphtoyl, carboxymethyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 4-isopropylbenzoyl, 3,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 4-methoxybenzoyl, 3,4,5-trimethoxybenzoyl, 4-hydroxybenzoyl, 4-benzyloxybenzoyl, 2-acetoxybenzoyl, 4-acetoxybenzoyl, 4-chlorobenzoyl, 2-(3-trifluoromethylphenylamino)benzoyl, 4-acetylaminobenzoyl.
8. A compound as in claim 1 wherein Ra is R9, Rb is R10 and Rc is R5.
9. A compound as in claim 8 wherein R5 is hydrogen or 2-acetoxyphenyl.
10. A compound as in claim 8 wherein R9 is pivaloyloxymethyl, 1-(pivaloyloxy)ethyl, phthalimidomethyl or 2-phthalimidoethyl.
11. A compound as in claim 8 wherein R10 is acetyl or benzoyl.
12. (4R)-2-(2-Methoxyphenyl)-3-(S-methyl-3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid of the formula of claim 1.
13. (4R)-2-(2-Acetoxyphenyl)-3-(S-acetyl-3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid of the formula of claim 1.
14. (4R)-2-(2-Hyroxyphenyl)-3-(S-pivaloyl-3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid of the formula of claim 1.
15. (4R)-3-[S-(4-Hydroxybenzoyl)-3-mercaptopropanoyl]-2-(2-hydroxyphenyl)-4-thiazolidinecabroxylic acid of the formula of claim 1.
16. A composition comprising (i) a compound of claim 1 in an amount sufficient to reduce blood pressure and (ii) pharmaceutically acceptable excipient(s).
17. A method for reducing blood pressure which comprises administering a composition comprising (i) a compound of claim 1 and (ii) pharmaceutically acceptable excipient(s).
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP53-135093 | 1978-10-31 | ||
| JP13509378A JPS5562060A (en) | 1978-10-31 | 1978-10-31 | Sulfur-containing compound |
| JP15516678A JPS5581854A (en) | 1978-12-14 | 1978-12-14 | Sulfur-containing compound |
| JP53-155166 | 1978-12-14 | ||
| JP54-012519 | 1979-02-06 | ||
| JP1251979A JPS55104275A (en) | 1979-02-06 | 1979-02-06 | Sulfur-containing compound |
| JP54-018812 | 1979-02-19 | ||
| JP1881279A JPS55111481A (en) | 1979-02-19 | 1979-02-19 | Ester type hypotensive agent |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/395,128 Division US4496578A (en) | 1978-10-31 | 1982-07-06 | Antihypertensive sulfur-containing compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4483861A true US4483861A (en) | 1984-11-20 |
Family
ID=27455824
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/086,996 Expired - Lifetime US4483861A (en) | 1978-10-31 | 1979-10-22 | Antihypertensive sulfur-containing compounds |
| US06/395,128 Expired - Fee Related US4496578A (en) | 1978-10-31 | 1982-07-06 | Antihypertensive sulfur-containing compounds |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/395,128 Expired - Fee Related US4496578A (en) | 1978-10-31 | 1982-07-06 | Antihypertensive sulfur-containing compounds |
Country Status (7)
| Country | Link |
|---|---|
| US (2) | US4483861A (en) |
| CH (1) | CH642351A5 (en) |
| DE (1) | DE2944037A1 (en) |
| FR (1) | FR2440365A1 (en) |
| GB (1) | GB2038800B (en) |
| IT (1) | IT1124841B (en) |
| SE (1) | SE448541B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4661515A (en) * | 1982-07-21 | 1987-04-28 | Usv Pharmaceutical Corporation | Compounds having angiotensin converting enzyme inhibitory activity and diuretic activity |
| US4692458A (en) * | 1980-03-05 | 1987-09-08 | University Of Miami | Anti-hypertensive agents |
| US4745124A (en) * | 1978-09-11 | 1988-05-17 | University Of Miami | Orally effective anti-hypertensive agents |
| US5214045A (en) * | 1989-07-14 | 1993-05-25 | Richter Gedeon Vegyeszeti Gyar Rt | Amino acid containing acrylamide derivatives for ulcer prevention or treatment |
| CN102573466A (en) * | 2009-04-22 | 2012-07-11 | 墨卡托医疗系统公司 | Use of local vascular delivery of guanethidine for the treatment of hypertension |
| US10849879B2 (en) | 2011-10-19 | 2020-12-01 | Mercator Medsystems, Inc. | Localized modulation of tissues and cells to enhance therapeutic effects including renal denervation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5683483A (en) * | 1979-12-13 | 1981-07-08 | Santen Pharmaceut Co Ltd | Thiazolidine compound |
| US4482725A (en) * | 1980-04-03 | 1984-11-13 | E. R. Squibb & Sons, Inc. | S-Acylation products of mercaptoacyl amino acids and carboxyl group containing diuretics |
| DE3152643A1 (en) * | 1980-12-29 | 1982-12-16 | Santen Pharmaceutical Co Ltd | HETEROCYCLIC 5-MEMBERED RING COMPOUNDS |
| JPS57112381A (en) * | 1980-12-29 | 1982-07-13 | Santen Pharmaceut Co Ltd | Five-membered heterocyclic compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4129571A (en) * | 1977-01-17 | 1978-12-12 | E. R. Squibb & Sons, Inc. | Amino acid derivatives |
| US4282235A (en) * | 1978-05-22 | 1981-08-04 | E. R. Squibb & Sons, Inc. | Derivatives of thiazolidinecarboxylic acids and related acids |
| US4386096A (en) * | 1978-04-08 | 1983-05-31 | Santen Pharmaceutical Co., Ltd. | Antihypertensive 4-thiazolidinecarboxylic acids (furyl and thienyl derivatives) |
| US4424228A (en) * | 1980-09-20 | 1984-01-03 | Santen Pharmaceutical Co., Ltd. | Antihypertensive agent comprising a thiazolidine carboxylic acid and probenecid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU509899B2 (en) * | 1976-02-13 | 1980-05-29 | E.R. Squibb & Sons, Inc. | Proline derivatives and related compounds |
| US4046889A (en) * | 1976-02-13 | 1977-09-06 | E. R. Squibb & Sons, Inc. | Azetidine-2-carboxylic acid derivatives |
| US4091024A (en) * | 1976-12-03 | 1978-05-23 | E. R. Squibb & Sons, Inc. | Pyrrolidine and piperidine-2-carboxylic acid derivatives |
| AU518147B2 (en) * | 1976-12-03 | 1981-09-17 | E.R. Squibb & Sons, Inc. | Derivatives of thiazolidine, thiazine and morpholine carboxylic acids |
| FR2395998A1 (en) * | 1977-06-29 | 1979-01-26 | Yoshitomi Pharmaceutical | NEW THIAZOLIDINE DERIVATIVES AND THEIR APPLICATION IN THE TREATMENT OF HYPERTENSION |
| JPS5834474B2 (en) * | 1977-06-29 | 1983-07-27 | ウェルファイド株式会社 | Method for producing thiazolidine derivatives |
| JPS5455565A (en) * | 1977-10-06 | 1979-05-02 | Santen Pharmaceut Co Ltd | Novel thiazolidine derivative |
| IT7851510A0 (en) * | 1977-10-28 | 1978-10-16 | Sandoz Ag | AMIDES OF CYCLIC AMINO ACIDS THEIR PREPARATION AND THEIR APPLICATION AS MEDICINES |
| US4233309A (en) * | 1977-12-06 | 1980-11-11 | Teijin Limited | Novel 1-substituted-3-acylpyrrole derivatives, platelet aggregation inhibitors containing them, as active ingredients, and processes for production of said derivatives |
| FR2412537A1 (en) * | 1977-12-22 | 1979-07-20 | Science Union & Cie | NEW SUBSTITUTE THIOBUTYRAMIDES, THEIR METHODS OF OBTAINING AND THEIR PHARMACEUTICAL APPLICATION |
| PH15381A (en) * | 1978-02-21 | 1982-12-17 | Squibb & Sons Inc | Halogen substituted mercaptoacylamino acids |
| JPS584711B2 (en) * | 1978-08-02 | 1983-01-27 | 参天製薬株式会社 | Pyrrolidine derivative |
| CA1144930A (en) * | 1978-08-11 | 1983-04-19 | Miguel A. Ondetti | Mercaptoacyl derivatives of substituted prolines |
| NL7809120A (en) * | 1978-09-07 | 1980-03-11 | Oce Andeno B V Grubbenvorsterw | PROCESS FOR THE PREPARATION OF PROLINE DERIVATIVES. |
| JPS5829950B2 (en) * | 1978-10-05 | 1983-06-25 | ウェルファイド株式会社 | Cyclic iminocarboxylic acid derivatives and their salts |
| US4290952A (en) * | 1980-06-23 | 1981-09-22 | American Home Products Corporation | Aryl-1-mercaptoalkanoylproline and homoproline derivatives |
-
1979
- 1979-10-22 US US06/086,996 patent/US4483861A/en not_active Expired - Lifetime
- 1979-10-25 GB GB7936988A patent/GB2038800B/en not_active Expired
- 1979-10-30 SE SE7908994A patent/SE448541B/en not_active IP Right Cessation
- 1979-10-30 IT IT26923/79A patent/IT1124841B/en active
- 1979-10-31 DE DE19792944037 patent/DE2944037A1/en active Granted
- 1979-10-31 CH CH977979A patent/CH642351A5/en not_active IP Right Cessation
- 1979-10-31 FR FR7926983A patent/FR2440365A1/en active Granted
-
1982
- 1982-07-06 US US06/395,128 patent/US4496578A/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4129571A (en) * | 1977-01-17 | 1978-12-12 | E. R. Squibb & Sons, Inc. | Amino acid derivatives |
| US4154960A (en) * | 1977-01-17 | 1979-05-15 | E. R. Squibb & Sons, Inc. | Amino acid derivatives |
| US4386096A (en) * | 1978-04-08 | 1983-05-31 | Santen Pharmaceutical Co., Ltd. | Antihypertensive 4-thiazolidinecarboxylic acids (furyl and thienyl derivatives) |
| US4423054A (en) * | 1978-04-08 | 1983-12-27 | Santen Pharmaceutical Co., Ltd. | Antihypertensive 4-thiazolidinecarboxylic acids (substituted alkyl derivatives) |
| US4282235A (en) * | 1978-05-22 | 1981-08-04 | E. R. Squibb & Sons, Inc. | Derivatives of thiazolidinecarboxylic acids and related acids |
| US4424228A (en) * | 1980-09-20 | 1984-01-03 | Santen Pharmaceutical Co., Ltd. | Antihypertensive agent comprising a thiazolidine carboxylic acid and probenecid |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4745124A (en) * | 1978-09-11 | 1988-05-17 | University Of Miami | Orally effective anti-hypertensive agents |
| US4692458A (en) * | 1980-03-05 | 1987-09-08 | University Of Miami | Anti-hypertensive agents |
| US4661515A (en) * | 1982-07-21 | 1987-04-28 | Usv Pharmaceutical Corporation | Compounds having angiotensin converting enzyme inhibitory activity and diuretic activity |
| US5214045A (en) * | 1989-07-14 | 1993-05-25 | Richter Gedeon Vegyeszeti Gyar Rt | Amino acid containing acrylamide derivatives for ulcer prevention or treatment |
| CN102573466A (en) * | 2009-04-22 | 2012-07-11 | 墨卡托医疗系统公司 | Use of local vascular delivery of guanethidine for the treatment of hypertension |
| US9011879B2 (en) | 2009-04-22 | 2015-04-21 | Mercator Medsystems, Inc. | Treatment of renal hypertension or carotid sinus syndrome with heated fluid sympathetic denervation or neuromodulation |
| US9199065B2 (en) | 2009-04-22 | 2015-12-01 | Mercator Medsystems, Inc. | Treatment of renal hypertension or carotid sinus syndrome with adventitial pharmaceutical sympathetic denervation or neuromodulation |
| US11083877B2 (en) | 2009-04-22 | 2021-08-10 | Mercator Medsystems, Inc. | Treatment of hypertension by renal vascular delivery of guanethidine |
| US10849879B2 (en) | 2011-10-19 | 2020-12-01 | Mercator Medsystems, Inc. | Localized modulation of tissues and cells to enhance therapeutic effects including renal denervation |
Also Published As
| Publication number | Publication date |
|---|---|
| SE7908994L (en) | 1980-05-01 |
| FR2440365B1 (en) | 1983-08-26 |
| DE2944037A1 (en) | 1980-05-08 |
| CH642351A5 (en) | 1984-04-13 |
| IT7926923A0 (en) | 1979-10-30 |
| FR2440365A1 (en) | 1980-05-30 |
| IT1124841B (en) | 1986-05-14 |
| US4496578A (en) | 1985-01-29 |
| DE2944037C2 (en) | 1988-04-14 |
| GB2038800A (en) | 1980-07-30 |
| GB2038800B (en) | 1983-05-05 |
| SE448541B (en) | 1987-03-02 |
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